Proanthocyanidins from cranberry fruit (Vaccinium macrocarpon) modulate colon tumor cell proliferation by multiple pathways

A-type proanthocyanidins (PACs) isolated from cranberry fruit (Vaccinium macrocarpon) are observed to decrease the proliferation of HCT116 and HT-29 colon cancer cells. FACS analysis shows that cell cycle arrest in G2 is significantly increased by exposure to PACs for as little as six hours. To determine the pathways affected by treatment, cells were exposed to cranberry PACs at 6 and 18 hours. Total RNA was extracted from treated and untreated control cells. Transcriptional profiling using an Illumina microarray system revealed altered expression of several members of the mitogen activated protein kinase family (MAPK) in treated cells, leading to decreased transcription of genes in the nucleus. Quantitative (Q)-PCR confirmed changes in expression of these genes, and changes in expression of MAPK pathway proteins (MAPK1/ERK, MAP2K1) were confirmed by Western blotting. PACs also appear to modulate apoptosis -linked genes (Bid, Bax and Bcl-family) and inflammation-linked genes (IL-4, IL-8, TNF-α, COX-2, CEACAM-1) suggesting multiple cellular targets for these compounds.